Changes in expression of ΔFosB and the Fos family proteins following NMDA receptor activation in the rat striatum

Abstract

Receptor-induced expression of transcription factors of the activator protein-1 (AP-1) family in neurons occurs in a unique temporal pattern which regulates subsequent downstream gene expression. We investigated the expression of the Fos family proteins following injection of the NMDA receptor agonist quinolinic acid (QA) into the rat striatum. The c-Fos protein is rapidly and transiently expressed, followed by the sequential and overlapping expression in the same striatal neurons of FosB, from 4 to 8 h post-lesion and ΔFosB from 6 h to beyond 30 h post-lesion. Analysis confirms that mRNA transcripts of both fosB and alternatively spliced ΔfosB are expressed in the striatum after QA lesion. The Fos-related antigens Fra-1 and Fra-2 and three previously uncharacterized c-Fos-related proteins were additionally found in the striatum which do not increase following lesion. These proteins are related to the highly conserved DNA-binding domain of c-Fos but are not immunologically related to the FosB protein as has been previously reported for proteins induced following chronic stimulation of the striatum. We additionally demonstrate that the c-Fos and ΔFosB proteins expressed following QA lesion bind to the functional AP-1 site in the promoter of the nerve growth factor (NGF) gene, the regulation of which temporally and spatially coincides with the AP-1 protein increases in the QA-lesioned striatum. However, the levels of binding to the NGF AP-1 site do not increase throughout time following lesion despite the induced expression of Fos family proteins, suggesting that the regulation of the NGF gene in this paradigm does not simply involve increased binding to the AP-1 site in the NGF gene promoter.